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Wren GH, Davies W. X-linked ichthyosis: New insights into a multi-system disorder. SKIN HEALTH AND DISEASE 2022; 2:e179. [PMID: 36479267 PMCID: PMC9720199 DOI: 10.1002/ski2.179] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/09/2022] [Indexed: 11/07/2022]
Abstract
Background X-linked ichthyosis (XLI) is a rare genetic condition almostexclusively affecting males; it is characterised by abnormal desquamation and retentionhyperkeratosis, and presents with polygonal brown scales. Most cases resultfrom genetic deletions within Xp22.31 spanning the STS (steroid sulfatase)gene, with the remaining cases resulting from STS-specific mutations. For manyyears it has been recognised that individuals with XLI are at increased risk ofcryptorchidism and corneal opacities. Methods We discuss emerging evidence that such individuals are alsomore likely to be affected by a range of neurodevelopmental and psychiatrictraits, by cardiac arrhythmias, and by rare fibrotic and bleeding-relatedconditions. We consider candidate mechanisms that may confer elevatedlikelihood of these individual conditions, and propose a novel commonbiological risk pathway. Results Understanding the prevalence, nature and co-occurrence ofcomorbidities associated with XLI is critical for ensuring early identificationof symptoms and for providing the most effective genetic counselling andmultidisciplinary care for affected individuals. Conclusion Future work in males with XLI, and in new preclinical andcellular model systems, should further clarify underlying pathophysiologicalmechanisms amenable to therapeutic intervention.
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Affiliation(s)
| | - William Davies
- School of PsychologyCardiff UniversityCardiffUK
- School of MedicineCardiff UniversityCardiffUK
- Centre for Neuropsychiatric Genetics and GenomicsCardiff UniversityCardiffUK
- Neuroscience and Mental Health Innovation InstituteCardiff UniversityCardiffUK
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Hazelgrove K. The role of the immune system in postpartum psychosis. Brain Behav Immun Health 2021; 18:100359. [PMID: 34704078 PMCID: PMC8521124 DOI: 10.1016/j.bbih.2021.100359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 09/22/2021] [Accepted: 09/27/2021] [Indexed: 02/06/2023] Open
Abstract
Postpartum psychosis is the most severe psychiatric disorder associated with childbirth. The risk is particularly high for women with a history of bipolar disorder or schizoaffective disorder, or those who have suffered a previous episode of postpartum psychosis. However, the aetiology of the illness remains unclear. Pregnancy and the early postpartum are times of significant immunological change. Furthermore, alterations to the immune system have been implicated in the onset and course of various psychopathologies, both related and unrelated to childbirth. Emerging evidence, from studies on immune related disorders, immune cells and inflammatory markers, suggests that the immune system might also be involved in the pathophysiology of postpartum psychosis. Furthermore, recent research has also begun to explore the potential mechanisms underlying immune dysfunction in postpartum psychosis (e.g., disturbances in the Treg-CCN3 protein-(re)myelination axis). Nevertheless, more research is required to understand whether immune dysfunction is a cause or consequence of postpartum psychosis and to clarify the exact mechanisms involved. The aim of this short review is to present the current findings on immune system dysregulation in postpartum psychosis, discuss possible mechanisms underlying the association, highlight potential challenges and confounders and provide suggestions for future research.
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Affiliation(s)
- Katie Hazelgrove
- Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
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3
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Davies W. The contribution of Xp22.31 gene dosage to Turner and Klinefelter syndromes and sex-biased phenotypes. Eur J Med Genet 2021; 64:104169. [PMID: 33610733 DOI: 10.1016/j.ejmg.2021.104169] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/11/2021] [Accepted: 02/16/2021] [Indexed: 11/27/2022]
Abstract
Turner syndrome (TS) is a rare developmental condition in females caused by complete, or partial, loss of the second sex chromosome; it is associated with a number of phenotypes including short stature, ovarian failure and infertility, as well as neurobehavioural and cognitive manifestations. In contrast, Klinefelter syndrome (KS) arises from an excess of X chromosome material in males (typical karyotype is 47,XXY); like TS, KS is associated with infertility and hormonal imbalance, and behavioural/neurocognitive differences from gonadal sex-matched counterparts. Lower dosage of genes that escape X-inactivation may partially explain TS phenotypes, whilst overdosage of these genes may contribute towards KS-related symptoms. Here, I discuss new findings from individuals with deletions or duplications limited to Xp22.31 (a region escaping X-inactivation), and consider the extent to which altered gene dosage within this small interval (and of the steroid sulfatase (STS) gene in particular) may influence the phenotypic profiles of TS and KS. The expression of X-escapees can be higher in female than male tissues; I conclude by considering how lower Xp22.31 gene dosage in males may increase their likelihood of exhibiting particular phenotypes relative to females. Understanding the genetic contribution to specific phenotypes in rare disorders such as TS and KS, and to more common sex-biased phenotypes, will be important for developing more effective, and more personalised, therapeutic approaches.
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Affiliation(s)
- William Davies
- School of Psychology, Cardiff University, Cardiff, UK; Division of Psychological Medicine and Clinical Neurosciences and Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
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Thippeswamy H, Davies W. A new molecular risk pathway for postpartum mood disorders: clues from steroid sulfatase-deficient individuals. Arch Womens Ment Health 2021; 24:391-401. [PMID: 33219387 PMCID: PMC8116278 DOI: 10.1007/s00737-020-01093-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 11/13/2020] [Indexed: 12/17/2022]
Abstract
Postpartum mood disorders develop shortly after childbirth in a significant proportion of women. These conditions are associated with a range of symptoms including abnormally high or low mood, irritability, cognitive disorganisation, disrupted sleep, hallucinations/delusions, and occasionally suicidal or infanticidal ideation; if not treated promptly, they can substantially impact upon the mother's health, mother-infant bonding, and family dynamics. The biological precipitants of such disorders remain unclear, although large changes in maternal immune and hormonal physiology following childbirth are likely to play a role. Pharmacological therapies for postpartum mood disorders can be effective, but may be associated with side effects, concerns relating to breastfeeding, and teratogenicity risks when used prophylactically. Furthermore, most of the drugs that are used to treat postpartum mood disorders are the same ones that are used to treat mood episodes during non-postpartum periods. A better understanding of the biological factors predisposing to postpartum mood disorders would allow for rational drug development, and the identification of predictive biomarkers to ensure that 'at risk' mothers receive earlier and more effective clinical management. We describe new findings relating to the role of the enzyme steroid sulfatase in maternal postpartum behavioural processes, and discuss how these point to a novel molecular risk pathway underlying postpartum mood disorders. Specifically, we suggest that aberrant steroid hormone-dependent regulation of neuronal calcium influx via extracellular matrix proteins and membrane receptors involved in responding to the cell's microenvironment might be important. Testing of this hypothesis might identify novel therapeutic targets and predictive biomarkers.
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Affiliation(s)
- Harish Thippeswamy
- Department of Psychiatry, National Institute of Mental Health and Neuro Sciences (NIMHANS), Bangalore, India
| | - William Davies
- Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK. .,School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK. .,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK.
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Davies W. An Analysis of Cellular Communication Network Factor Proteins as Candidate Mediators of Postpartum Psychosis Risk. Front Psychiatry 2019; 10:876. [PMID: 31849729 PMCID: PMC6901936 DOI: 10.3389/fpsyt.2019.00876] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 11/06/2019] [Indexed: 12/21/2022] Open
Abstract
Postpartum (or puerperal) psychosis (PP) is a severe psychiatric condition associated with hallucinations, delusions, cognitive disorganization, and mood problems, which affects approximately 1-2 out of every 1,000 mothers shortly after childbirth. While the risk factors for, and co-morbidities of, PP are relatively well-defined, currently, the pathophysiology underlying the disorder is very poorly-specified. Here, I argue, on the basis of multiple lines of new evidence, that altered expression of the Cellular Communication Network (CCN) factor proteins (and of the heterodimerizing CCN2 and CCN3 proteins in particular), may be associated with, and possibly causal for, increased PP risk. Future preclinical and clinical studies should aim to test this hypothesis as empirical support for it would provide much-needed clues regarding the biological substrates of PP, and could point to predictive biomarkers for the condition.
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Affiliation(s)
- William Davies
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
- School of Psychology, Cardiff University, Cardiff, United Kingdom
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
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Humby T, Davies W. Brain Gene Expression in a Novel Mouse Model of Postpartum Mood Disorder. Transl Neurosci 2019; 10:168-174. [PMID: 31410299 PMCID: PMC6689211 DOI: 10.1515/tnsci-2019-0030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 06/26/2019] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Steroid sulfatase (STS) cleaves sulfate groups from steroid hormones; its expression/activity increases in late pregnancy and into the postpartum period. STS-deficient human and mouse mothers display elevated psychopathology and abnormal behaviour respectively; in mice, these effects can be partially normalised by antipsychotic (ziprasidone) administration. METHODOLOGY We compared brain gene expression in new mouse mothers administered the STS inhibitor 667-Coumate, or vehicle; significant changes were followed-up with pathway analysis and quantitative polymerase chain reaction (qPCR). Finally, the effects of combined 667-Coumate and ziprasidone administration on expression of the most robustly differentially-expressed genes were examined. RESULTS Surprisingly, no between-group gene expression changes were detected at a False Discovery Rate (FDR)-corrected p<0.1. 1,081 unique expression changes were detected at p<0.05, two top hits were verified by qPCR, and pathway analysis indicated enrichment of genes involved in olfactory transduction. The expression of Stoml3 and Cyp2g1 was unaffected by ziprasidone administration. CONCLUSIONS Postpartum behavioural abnormalities in STS-deficient mothers are likely to be the culmination of many small gene expression changes. Our data are consistent with the idea that olfactory function is key to maternal behaviour in mice, and suggest that aberrant expression of olfactory system genes may underlie abnormal maternal behaviour in STS-deficient women.
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Affiliation(s)
- Trevor Humby
- School of Psychology, Cardiff University, Cardiff CF10 3AT, Cardiff, UK
- Neuroscience and Mental Health Research Institute, Cardiff University, CardiffCF24 4HQ, UK
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CardiffCF24 4HQ, UK
| | - William Davies
- School of Psychology, Cardiff University, Cardiff CF10 3AT, Cardiff, UK
- Neuroscience and Mental Health Research Institute, Cardiff University, CardiffCF24 4HQ, UK
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, CardiffCF24 4HQ, UK
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Cavenagh A, Chatterjee S, Davies W. Behavioural and psychiatric phenotypes in female carriers of genetic mutations associated with X-linked ichthyosis. PLoS One 2019; 14:e0212330. [PMID: 30768640 PMCID: PMC6377116 DOI: 10.1371/journal.pone.0212330] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 01/31/2019] [Indexed: 12/12/2022] Open
Abstract
X-linked ichthyosis (XLI) is a rare X-linked dermatological condition arising from deficiency for the enzyme steroid sulfatase (STS). STS is normally expressed in the brain, and males with XLI exhibit personality differences from males in the general population, and are at increased risk of developmental and mood disorders. As the STS gene escapes X-inactivation, female carriers of XLI-associated genetic mutations have reduced STS expression/activity relative to non-carrier females, and could manifest similar behavioural phenotypes to males with XLI. Additionally, as STS activity normally increases in female tissues towards late pregnancy and into the puerperium, carrier females could theoretically present with increased rates of postpartum psychopathology. Using a worldwide online survey comprising custom-designed demographic questionnaires and multiple validated psychological questionnaires, we collected detailed self-reported information on non-postpartum and postpartum behaviour in confirmed adult (>16yrs) female carriers of genetic mutations associated with XLI (n = 94) for statistical comparison to demographically-matched previously-published normative data from female controls (seven independent studies, 98≤n≤2562), adult males with XLI (n = 58), and to newly-obtained online survey data from a general population sample of mothers from the United Kingdom and United States of America (n = 263). The pattern of results in carrier females relative to controls was remarkably similar to that previously observed in males with XLI, with evidence for increased rates of developmental and mood disorders, and elevated levels of inattention, impulsivity, autism-related traits and general psychological distress. Carrier females exhibited a significantly elevated rate of postpartum mental health conditions (notably mild depression) relative to controls which could not be accounted for by social factors. Our data confirm the psychological profile associated with XLI-associated mutations, and suggest that female carriers may be at increased risk of psychopathology, including in the postpartum period. These findings are relevant to families affected by XLI, to clinicians involved in the care of these families, and to genetic counsellors.
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Affiliation(s)
- Alice Cavenagh
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Sohini Chatterjee
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - William Davies
- MRC Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, United Kingdom
- School of Psychology, Cardiff University, Cardiff, United Kingdom
- Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, United Kingdom
- * E-mail:
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Dazzan P, Fusté M, Davies W. Do Defective Immune System-Mediated Myelination Processes Increase Postpartum Psychosis Risk? Trends Mol Med 2018; 24:942-949. [PMID: 30348609 PMCID: PMC6224363 DOI: 10.1016/j.molmed.2018.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/12/2018] [Accepted: 09/14/2018] [Indexed: 12/17/2022]
Abstract
Postpartum (or puerperal) psychosis (PP) is a rare, severe psychiatric disorder that affects women shortly after childbirth; risk is particularly high in individuals with a history of bipolar disorder or PP, but the underlying pathophysiology remains poorly understood. Emerging evidence suggests that immune system (dys)function plays an important role in disorder onset. On the basis of new findings from clinical and animal model studies, we hypothesise that the abundance and/or activity of regulatory T cells, and the efficacy of consequent (re)myelination processes in the brain mediated by CCN proteins, is perturbed in PP; this pathway may be modulated by risk and protective/treatment factors for the disorder, and identifying abnormalities within it could signpost novel predictive biomarkers and therapeutic targets.
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Affiliation(s)
- Paola Dazzan
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK; National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London, London, UK
| | - Montserrat Fusté
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
| | - William Davies
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Neuroscience and Mental Health Research Institute, Schools of Medicine and Psychology, Cardiff University, Cardiff, UK.
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Davies W. SULFATION PATHWAYS: The steroid sulfate axis and its relationship to maternal behaviour and mental health. J Mol Endocrinol 2018; 61:T199-T210. [PMID: 29440314 DOI: 10.1530/jme-17-0219] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 11/16/2017] [Indexed: 12/14/2022]
Abstract
Steroid hormones can exist in functionally dissociable sulfated and non-sulfated (free) forms and can exert profound effects on numerous aspects of mammalian physiology; the ratio of free-to-sulfated steroids is governed by the antagonistic actions of steroid sulfatase (STS) and sulfotransferase (SULT) enzymes. Here, I examine evidence from human and animal model studies, which suggests that STS and its major substrate (dehydroepiandrosterone sulfate, DHEAS) and product (DHEA) can influence brain function, behaviour and mental health, before summarising how the activity of this axis varies throughout mammalian pregnancy and the postpartum period. I then consider how the steroid sulfate axis might impact upon normal maternal behaviour and how its dysfunction might contribute towards risk of postpartum psychiatric illness. Understanding the biological substrates underlying normal and abnormal maternal behaviour will be important for maximising the wellbeing of new mothers and their offspring.
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Affiliation(s)
- William Davies
- School of PsychologyCardiff University, Cardiff, UK
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical NeurosciencesSchool of Medicine, Cardiff University, Cardiff, UK
- Neuroscience and Mental Health Research InstituteCardiff University, Cardiff, UK
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Malik A, Amer AB, Salama M, Haddad B, Alrifai MT, Balwi MA, Davies W, Eyaid W. X-linked ichthyosis associated with psychosis and behavioral abnormalities: a case report. J Med Case Rep 2017; 11:267. [PMID: 28934990 PMCID: PMC5609014 DOI: 10.1186/s13256-017-1420-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 08/08/2017] [Indexed: 01/21/2023] Open
Abstract
Background X-linked ichthyosis is a dermatological condition caused by deficiency for the enzyme steroid sulfatase. Previously, X-linked ichthyosis/steroid sulfatase deficiency has been associated with developmental and neurological phenotypes. Here, we show for the first time, that X-linked ichthyosis may be comorbid with an additional psychiatric phenotype (psychosis). Case presentation We report the case of an 11-year-old Saudi Arabian boy with X-linked ichthyosis associated with psychosis, mental retardation, autism spectrum disorder, inattentive attention deficit hyperactivity disorder, and epilepsy. Genetic analysis revealed a 1.68 Mb deletion encompassing STS in 95% of cells while biochemical analysis revealed correspondingly low steroid sulfatase activity consistent with a diagnosis of X-linked ichthyosis. The psychotic symptoms could be reasonably well controlled by administration of an atypical antipsychotic. Conclusions This report describes a case of comorbid X-linked ichthyosis and psychosis (most closely corresponding to early-onset schizophrenia) for the first time, and suggests that deficiency for steroid sulfatase and contiguous genes may increase vulnerability to psychosis as well as other psychological disorders.
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Affiliation(s)
- Amna Malik
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.,King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia.,King AbdulAziz Medical City, Riyadh, Saudi Arabia
| | - Ahmed Bait Amer
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.,King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia.,King AbdulAziz Medical City, Riyadh, Saudi Arabia
| | - Mohammed Salama
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.,King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia.,King AbdulAziz Medical City, Riyadh, Saudi Arabia
| | - Bander Haddad
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.,King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia.,King AbdulAziz Medical City, Riyadh, Saudi Arabia
| | - Muhammad T Alrifai
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.,King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia.,King AbdulAziz Medical City, Riyadh, Saudi Arabia
| | - Mohammed Al Balwi
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.,King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia.,King AbdulAziz Medical City, Riyadh, Saudi Arabia
| | - William Davies
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK. .,School of Psychology, Cardiff University, Cardiff, UK. .,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK. .,MRC Centre for Neuropsychiatric Genetics and Genomics, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
| | - Wafaa Eyaid
- King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia. .,King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia. .,King AbdulAziz Medical City, Riyadh, Saudi Arabia. .,Department of Pediatrics MC 1510, King AbdulAziz Medical City, King Fahad National Guard Hospital, P.O Box 22490, Riyadh, 11426, Saudi Arabia.
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Davies W. Understanding the pathophysiology of postpartum psychosis: Challenges and new approaches. World J Psychiatry 2017; 7:77-88. [PMID: 28713685 PMCID: PMC5491479 DOI: 10.5498/wjp.v7.i2.77] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 01/25/2017] [Accepted: 04/20/2017] [Indexed: 02/05/2023] Open
Abstract
Postpartum psychosis is a severe psychiatric condition which affects 1-2 of every 1000 mothers shortly after childbirth. Whilst there is convincing evidence that the condition is precipitated by a complex combination of biological and environmental factors, as yet the pathophysiological mechanisms remain extremely poorly defined. Here, I critically review approaches that have been, or are being, employed to identify and characterise such mechanisms; I also review a recent animal model approach, and describe a novel biological risk model that it suggests. Clarification of biological risk mechanisms underlying disorder risk should permit the identification of relevant predictive biomarkers which will ensure that “at risk” subjects receive prompt clinical intervention if required.
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Humby T, Cross ES, Messer L, Guerrero S, Davies W. A pharmacological mouse model suggests a novel risk pathway for postpartum psychosis. Psychoneuroendocrinology 2016; 74:363-370. [PMID: 27728876 PMCID: PMC5094271 DOI: 10.1016/j.psyneuen.2016.09.019] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/08/2016] [Accepted: 09/21/2016] [Indexed: 01/04/2023]
Abstract
Postpartum psychosis (PP) is a severe psychiatric disorder affecting a small proportion of new mothers shortly after childbirth. The molecular pathophysiology underlying the disorder is currently poorly understood, and there are no amenable animal models for the condition; maternal deficiency for the enzyme steroid sulfatase has been proposed as a potential risk mechanism. Here we show that inhibition of steroid sulfatase with 667-COUMATE (10mg/kg p.o.) in new mouse mothers results in behavioural abnormalities that can be partially alleviated by the administration of the clinically-efficacious antipsychotic ziprasidone (0.3-1.0mg/kg i.p.). The pattern of behavioural abnormalities in 667-COUMATE-treated mice implicated a genetic substrate at 21-23cM on chromosome 15; of the 17 genes within this chromosomal interval, only one (Nov/Ccn3) was significantly differentially expressed in the brains of vehicle and 667-COUMATE-treated mice. Two additional members of the Ccn family (Ccn2/Ctgf and Ccn4/Wisp1) were also significantly differentially expressed between the two groups, as were three further genes co-expressed with Nov/Ccn3 in brain (Arhgdig) or previously implicated in disorder risk by clinical studies (Adcy8 and Ccl2). The expression of Nov/Ccn3, but not of the other differentially-expressed genes, could be normalised by ziprasidone administration (1.0mg/kg). NOV/CCN3 lies directly under a linkage peak for PP risk at 8q24, and the associated protein possesses numerous characteristics that make it an excellent candidate mediator of PP risk. Our data suggest the 667-COUMATE-treated mouse as a model for PP with some degree of face, construct, and predictive validity, and implicate a novel, and biologically-plausible, molecular risk pathway for PP.
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Affiliation(s)
- Trevor Humby
- School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
| | - Ellen S. Cross
- Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK
| | - Lauren Messer
- School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK.
| | - Silvia Guerrero
- University of Barcelona, Gran Via de les Corts Catalanes, 585 08007 Barcelona, Spain.
| | - William Davies
- School of Psychology, Cardiff University, Tower Building, 70, Park Place, Cardiff, CF10 3AT, UK; Neuroscience and Mental Health Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
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Davies W, Humby T, Trent S, Eddy JB, Ojarikre OA, Wilkinson LS. Genetic and pharmacological modulation of the steroid sulfatase axis improves response control; comparison with drugs used in ADHD. Neuropsychopharmacology 2014; 39:2622-32. [PMID: 24842408 PMCID: PMC4140762 DOI: 10.1038/npp.2014.115] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 04/10/2014] [Accepted: 05/02/2014] [Indexed: 02/08/2023]
Abstract
Maladaptive response control is a feature of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase (STS) influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,X(Y*)O mouse model, or pharmacological manipulation of the STS axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analog of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a prepotent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicates that the STS axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. While the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent.
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Affiliation(s)
- William Davies
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
| | - Trevor Humby
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
| | - Simon Trent
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
| | - Jessica B Eddy
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK
| | - Obah A Ojarikre
- MRC National Institute for Medical Research, London, Cardiff, UK
| | - Lawrence S Wilkinson
- Behavioral Genetics Group, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,MRC Centre for Neuropsychiatric Genetics and Genomics and Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK,Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK,School of Psychology, Cardiff University, Tower Building, Cardiff CF10 3AT, UK, Tel: +44 (0)29 2087 0357, Fax: +44 (0)29 2087 4858, E-mail:
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14
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Davies W. Sex differences in attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms. Front Neuroendocrinol 2014; 35:331-46. [PMID: 24680800 DOI: 10.1016/j.yfrne.2014.03.003] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Revised: 02/13/2014] [Accepted: 03/17/2014] [Indexed: 02/07/2023]
Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised by severe inattention, pathological impulsivity and hyperactivity; it is relatively common affecting up to 6% of children, and is associated with a risk of long-term adverse educational and social consequences. Males are considerably more likely to be diagnosed with ADHD than females; the course of the disorder and its associated co-morbidities also appear to be sensitive to sex. Here, I discuss fundamental biological (genetic and endocrine) mechanisms that have been shown to, or could theoretically, contribute towards these sexually dimorphic phenomena. Greater understanding of how and why the sexes differ with respect to ADHD vulnerability should allow us to identify and characterise novel protective and risk factors for the disorder, and should ultimately facilitate improved diagnosis, prognosis and treatment.
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Affiliation(s)
- William Davies
- Behavioural Genetics Group, Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Tower Building, Park Place, Cardiff CF10 3AT, UK; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
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15
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Elias PM, Williams ML, Choi EH, Feingold KR. Role of cholesterol sulfate in epidermal structure and function: lessons from X-linked ichthyosis. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1841:353-61. [PMID: 24291327 DOI: 10.1016/j.bbalip.2013.11.009] [Citation(s) in RCA: 83] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 11/13/2013] [Accepted: 11/20/2013] [Indexed: 02/07/2023]
Abstract
X-linked ichthyosis is a relatively common syndromic form of ichthyosis most often due to deletions in the gene encoding the microsomal enzyme, steroid sulfatase, located on the short area of the X chromosome. Syndromic features are mild or unapparent unless contiguous genes are affected. In normal epidermis, cholesterol sulfate is generated by cholesterol sulfotransferase (SULT2B1b), but desulfated in the outer epidermis, together forming a 'cholesterol sulfate cycle' that potently regulates epidermal differentiation, barrier function and desquamation. In XLI, cholesterol sulfate levels my exceed 10% of total lipid mass (≈1% of total weight). Multiple cellular and biochemical processes contribute to the pathogenesis of the barrier abnormality and scaling phenotype in XLI. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.
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Affiliation(s)
- Peter M Elias
- Dermatology Service, Department of Veterans Affairs Medical Center, and Department of Dermatology, University of California, San Francisco, CA USA.
| | - Mary L Williams
- Departments of Dermatology and Pediatrics, University of California, San Francisco, CA USA
| | - Eung-Ho Choi
- Department of Dermatology, Yonsei University, Wonju College of Medicine, Wonju, South Korea
| | - Kenneth R Feingold
- Medical Service, Department of Veterans Affairs Medical Center, and Department of Medicine, University of California, San Francisco, CA, USA
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16
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Trent S, Dean R, Veit B, Cassano T, Bedse G, Ojarikre OA, Humby T, Davies W. Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder. Psychoneuroendocrinology 2013; 38:1370-80. [PMID: 23276394 PMCID: PMC3690523 DOI: 10.1016/j.psyneuen.2012.12.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 12/03/2012] [Accepted: 12/04/2012] [Indexed: 12/23/2022]
Abstract
Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,X(Y*)O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,X(Y*)O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a 'foraging' task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or 'ability to wait', it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,X(Y*)O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,X(Y*)O model.
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Affiliation(s)
- Simon Trent
- Behavioural Genetics Group and Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | - Rachel Dean
- School of Psychology, Cardiff University, Cardiff, UK
| | - Bonnie Veit
- School of Psychology, Cardiff University, Cardiff, UK
| | - Tommaso Cassano
- Department of Clinical and Experimental Medicine, Medical School, University of Foggia, Foggia, Italy
| | - Gaurav Bedse
- Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy
| | - Obah A. Ojarikre
- Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, London, UK
| | - Trevor Humby
- Behavioural Genetics Group and Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK
| | - William Davies
- Behavioural Genetics Group and Neuroscience and Mental Health Research Institute, Schools of Psychology and Medicine, Cardiff University, Cardiff, UK,Institute of Psychological Medicine and Clinical Neurosciences and MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, UK,Corresponding author at: Henry Wellcome Building, Heath Park Campus, Cardiff CF14 4XN, UK. Tel.: +44 0 29 2068 7047; fax: +44 0 29 2068 7068.
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17
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Trent S, Davies W. Cognitive, behavioural and psychiatric phenotypes associated with steroid sulfatase deficiency. World J Transl Med 2013; 2:1-12. [DOI: 10.5528/wjtm.v2.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 01/24/2013] [Accepted: 02/08/2013] [Indexed: 02/05/2023] Open
Abstract
The enzyme steroid sulfatase (STS) desulfates a variety of steroid compounds thereby altering their activity. STS is expressed in the skin, and its deficiency in this tissue has been linked to the dermatological condition X-linked ichthyosis. STS is also highly expressed in the developing and adult human brain, and in a variety of steroidogenic organs (including the placenta and gonads); therefore it has the potential to influence brain development and function directly and/or indirectly (through influencing the hormonal milieu). In this review, we first discuss evidence from human and animal model studies suggesting that STS deficiency might predispose to neurobehavioural abnormalities and certain psychiatric disorders. We subsequently discuss potential mechanisms that may underlie these vulnerabilities. The data described herein have potential implications for understanding the complete spectrum of clinical phenotypes associated with X-linked ichthyosis, and may indicate novel pathogenic mechanisms underlying psychological dysfunction in developmental disorders such as attention deficit hyperactivity disorder and Turner syndrome.
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